Proinsulin, the biosynthetic precursor of insulin, comprises only 2-5% of extracted pancreatic immunoreactive insulin levels but may constitute up to 40-50% of plasma immunoreactive insulin levels in the basal state, suggesting a preferential secretion of proinsulin after an overnight fast. Since proinsulin appears to have less than 20% of the biological activity of insulin in previous studies, the purpose of this proposal is to further elucidate the possible significance of extra-pancreatic proinsulin levels by in vivo experiments in swine. This model is being used because of the availability of purified porcine insulin and proinsulin and three radioimmunoassays that will allow direct quantification of proinsulin, C-peptide and insulin after endogenous secretion or exogenous administration of these hormones. A possible synergistic effect of proinsulin and insulin on glucose, free fatty acid and amino acid levels (alpha-amino nitrogen), will be studied by doubling basal proinsulin or insulin levels with a continuous infusion of proinsulin or insulin followed at various time intervals with submaximal insulin and proinsulin injections. A qualitative difference in the effects of proinsulin and insulin on glucose production and utilization will be investigated by glucose turnover studies with glucose-1-C14, and measurements of glucose, free fatty acid and amino acid (alpha-amino nitrogen) levels after proinsulin and insulin injections.